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The bumpy road of purinergic inhibitors to clinical application in immune-mediated diseases

Neural Regeneration Research 2024年第6期19卷 1206-1211页

作者： Matihias T.Wyss Christine Heuer Marina Herwerth Institute of Pharmacology and Toxicology University of Zurich Neuroscience Center Zurich (ZNZ) University of Zurich and ETH Zurich 3. Neurology Department University Hospital of Zurich

Purinergic signaling plays important roles throughout the body in the regulation of organ functions during and following the disruption of homeostasis. This is also reflected by the widespread expression of two families of purinergic receptors(P1 and P2) with numerous subtypes. In the last few decades, there has been increasing evidence that purinergic signaling plays an important role in the regulation of immune functions. Mainly, signals mediated by P2 receptors have been shown to contribute to immune system-mediated pathologies. Thus, interference with P2 receptors may be a promising strategy for the modulation of immune responses. Although only a few clinical studies have been conducted in isolated entities with limited success, preclinical work suggests that the use of P2 receptor inhibitors may bear some promise in various autoimmune diseases. Despite the association of P2 receptors with several disorders from this field, the use of P2 receptor antagonists in clinical therapy is still very scarce. In this narrative review, we briefly review the involvement of the purinergic system in immunological responses and clinical studies on the effect of purinergic inhibition on autoimmune processes. We then open the aperture a bit and show some preclinical studies demonstrating a potential effect of purinergic blockade on autoimmune events. Using suramin, a non-specific purinergic inhibitor, as an example, we further show that off-target effects could be responsible for observed effects in immunological settings, which may have interesting implications. Overall, we believe that it is worthwhile to further investigate this hitherto underexplored area.

关键词： autoimmune diseases neurological disorders purinergic system P2 receptor inhibitors suramin

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suramin Inhibits the In Vitro Expression of Encephalitis B Virus Proteins NS3 and E

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2003年第4期23卷 375-379页

作者：徐可树任宏宇朱剑文杨昀廖芳 Department of Gastroenterology Department of Microbiology

In this study, the mechanism by which suramin inhibits the replication of epidemic encephalitis B virus was explored to provide a theoretical basis for its further application in clinical practice. After viral infection of HepG2 and IMR 32 cells, different concentrations of suramin were added to the culture media, and then the cultural supernatants and infected cells were collected 48 h later. For the evaluation of the curative effect, cytopathic effect (CPE), virus titers, the expression of viral protein and viral RNA were determined by Western blot, RT PCR and in vitro RNA synthesis, respectively. At the concentration of 50 μg/ml of suramin, HepG2 and IMR 32 infected with epidemic encephalitis B virus decreased by 51.8 % and 0.03 % respectively, as compared with controls. It was suggested that expression of encephalitis B virus proteins NS3 and E was notably reduced by suramin. This is especially true of E protein. At RNA level, however, no difference in RNA virus was found between suramin treated virus and non treated cells. Our results suggest that suramin can inhibit viral replication by blocking the production of viral proteins.

关键词： suramin antiviral activity encephalitis B virus

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suramin ACTIVITY IN HUMAN HEAD AND NECK SQUAMOUS CELL CARCINOMA

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山东大学学报(医学版) 1992年第3期 263-269页

作者：李安太王天铎栾信庸姜玉芳 Gus A.M.S.van dongen Boudewijn J.M.Braakhuis Gordon B.Snow The Netherlands Free University Hospital Amsterdam Dept.of Otolaryngology Affiliated Hospital of Shandong Medical University Dept.of Otolaryngology/Head and Neck Surgery

suramin,a drug used for the treatment of African trypanosomi-asis and onchoceriasis,has potential anti-cancer activity.In the present study.the effect of suramin on proliferation of human head and neck squamous cellcarcinoma cells was determined.A significant growth inhibition in all threecell lines tested was observed when the concentration of suramin was 100μg/ml or more.The hypothesis was tested whether growth inhibition may bedue to selective interference with the action of epidermal growth factor.suraminat growth inhibiting concentrations only partly antagonized the growth slimulat-ing effect of EGF at concentrations as low as 0.1 ng/ml,indicating that alsoother mechanisms of action may contribute to the growth inhibitory activity ofsuramin.Furthermore,evidence was found that also serum proteins other thangrowth factors presented in the culture medium have a growth stimulating effecton cells and a strongly antagonistical effect on suramin activity.

关键词： suramin Head and neck neoplasms Cell line

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Development of a C3c-based ELISA method for the determination of anti-complementary potency of Bupleurum polysaccharides

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Acta Pharmaceutica Sinica B 2015年第4期5卷 316-322页

作者： Mulu Wu Hong Li Yunyi Zhang Daofeng Chen Department of Pharmacology School of Pharmacy Fudan University Department of Microbiology Yong Loo Lin School of Medicine National University of Singapore Department of Pharmacognosy School of Pharmacy Fudan University

Traditionally, determination of inhibitory potency of complement inhibitors is performed by the hemolytic assay. However, this assay is not applicable to the lectin pathway, thus impeding the understanding of complement inhibitors against the overall function of the complement system. The main objective of our study was to develop a specific enzyme-linked immunosorbent assay(ELISA) as an alternative method to assess the anti-complement activity, particularly against the lectin pathway. By using respective coating substrates against different activation pathways, followed by capturing the stable C3c fragments, our ELISA method can be used to screen complement inhibitors against the classical pathway and the lectin pathway. The inhibitory effect of suramin on the classical pathway, as measured by our hemolytic assay is consistent with previous reports. Further assessment of suramin and Bupleurum polysaccharides against the lectin pathway showed a good reproducibility of the method. Comparison of the lectin pathway IC50 between Bupleurum smithii var. parvifolium polysaccharides(1.055 mg/mL) and Bupleurum chinense polysaccharides(0.98 mg/mL) showed that, similar to the classical and alterative pathway, these two Bupleurum polysaccharides had comparable anti-complementary properties against the lectin pathway. The results demonstrate that the described ELISA assay can compensate for the shortcomings of the hemolytic assay in lectin pathway.

关键词： ELISA Complement C3c suramin Bupleurum smithii var parvifolium Bupleurum chinense Polysaccharides

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大鼠海马CA1区神经元P2X受体对ATP、suramin的反应

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第三军医大学学报 2005年第16期27卷 1674-1677页

作者：赵延东阮怀珍第三军医大学基础医学部神经生物学教研室重庆市神经科学研究所重庆400038

目的研究大鼠海马CA1区神经元P2X受体对ATP的反应和suram in、iverm ectin(IVM)及低pH值对诱发电流的影响。方法采用酶加机械分离法分离后7 d的W istar大鼠海马CA1区锥体细胞,用膜片钳全细胞记录技术测定P2X受体激动剂ATP,阻断剂suram ... 详细信息

目的研究大鼠海马CA1区神经元P2X受体对ATP的反应和suram in、iverm ectin(IVM)及低pH值对诱发电流的影响。方法采用酶加机械分离法分离后7 d的W istar大鼠海马CA1区锥体细胞,用膜片钳全细胞记录技术测定P2X受体激动剂ATP,阻断剂suram in,调节剂iverm ectin(IVM)及低pH值(pH=6.5)对跨膜电流的作用。结果分离神经元对P2X受体激动剂和阻断剂反应明显,P2X受体调节剂对不同细胞有不同的作用。结论大鼠海马CA1区锥体细胞有丰富的P2X受体表达。细胞间P2X受体的表达类型有一定差别。

关键词： P2X受体海马膜片钳 ATP suramin

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An Odyssey in antiviral drug development—50 years at the Rega Institute:1964–2014

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Acta Pharmaceutica Sinica B 2015年第6期5卷 520-543页

作者： Erik De Clercq Rega Institute for Medical Research

I.How it started I entered the Rega Institute for Medical Research in August 1964,as a medical student,to start working under the guidance of Prof.Piet De Somer,then professor of microbiology at the Leuven School of M... 详细信息

关键词： Antiviral drug Atripla® Brivudin Complera®/Eviplera® Erik De Clercq FV-100 Holý's legacy Interferon Mozobil® Poly(I)·poly(C) Polyacrylic acid Reverse transcriptase Sofosbuvir Stavudine Stribild® suramin Tenofovir alafenamide (TAF) Tenofovir disoproxil fumarate (TDF) Truvada® Valaciclovir

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suramin作为预防艾滋病多效杀微生物剂的研究

Suramin作为预防艾滋病多效杀微生物剂的研究

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作者：李锦清南方医科大学

学位级别：硕士

研究背景:艾滋病(Acquired immunodeficiency sydrom,AIDS)是由人类免疫缺陷病毒(Human immunodeficiency virus type 1,HIV-1)引起的一种免疫能力丧失的传染性疾病,严重威胁着人类的生命和健康。全球范围内,新感染病例数居高不下,其中... 详细信息

研究背景:艾滋病(Acquired immunodeficiency sydrom,AIDS)是由人类免疫缺陷病毒(Human immunodeficiency virus type 1,HIV-1)引起的一种免疫能力丧失的传染性疾病,严重威胁着人类的生命和健康。全球范围内,新感染病例数居高不下,其中80%新感染病例来自性传播,性传播已成为HIV-1最主要的传播途径。杀微生物剂是种有效预防HIV-1性传播的重要手段。但迄今为止,仍未开发出有效的杀微生物剂。精液来源的病毒增强因子(SEVI)能削弱杀微生物剂的抗病毒活性同时显著促进病毒的感染。SEVI是前列腺酸性磷酸酶(PAP)裂解的多肽片段PAP248-286自我组装形成的淀粉样纤维。SEVI的阳离子特性能消除病毒和细胞的静电排斥,增大病毒和靶细胞接触几率,从而增强HIV-1感染。因此,SEVI是杀微生物剂的一个重要靶点。我们前期研究表明,HIV-1进入抑制剂ADS-J1既能拮抗SEVI,与抗病毒药物合用具有协同抗病毒效果。但由于ADS-J1具有潜在的致癌性,限制了它的临床应用。我们在ADS-J1类似物中筛选到一个本身具有抗HIV-1活性的化合物suramin,它是临床治疗锥虫病的经典老药,具有强大的药理活性:抑制蛋白酶和阻断生长因子等。前期研究表明,suramin能抑制多肽PAP248-286形成SEVI,本文将深入研究suramin抑制及拮抗SEVI的作用及机制;由于suramin本身具有抗HIV-1活性,我们也将探讨其与抗病毒药物合用协同抗病毒效果,期望将suramin开发为杀微生物剂或其辅助用药,更好地预防HIV-1性传播。研究目的从具备拮抗HIV-1性传播过程作用多靶点能力的角度阐述suramin用于预防HIV-1性传播的新的可能及机制,从老药新用的角度寻求扩大suramin临床适应症,为预防HIV-1性传播的杀微生物剂研发提供新的研究思路。研究方法1.刚果红染色、透射电镜、激光共聚焦显微镜、圆二色谱、Western blot和病毒感染实验方法检测suramin对SEVI形成及纤维本身的影响。2.病毒感染实验检测suramin合用抗逆转录病毒药物(ARVs)的抗病毒效果。3.XTT法检测suramin对生殖道和淋巴细胞的毒性作用。通过家兔阴道粘膜刺激性实验,suramin凝胶剂进行安全性初步评价,其中包括组织病理学检查、ELISA法检测阴道灌洗液细胞因子表达水平和PCNA免疫组化评价家兔阴道组织的炎症。4.多肽PAP248-286与suramin进行分子动力学(MD)模拟,从分子动力学角度证明suramin抑制SEVI形成机制。研究结果1.suramin能浓度依赖性抑制多肽PAP248-286纤维化;suramin能结合SEVI,阻断它和HIV-1的结合,降低SEVI促进HIV-1的感染能力。2.suramin在精液中联合ARVs可以抑制CCR5受体和CXCR4受体嗜性HIV-1,50%抑制率时的联合指数CI值范围为0.233-0.739。3.suramin在体外对生殖道细胞和淋巴细胞基本没有毒性作用,它对各细胞系的CC50均大于1000 μM。组织病理学检查结果显示suramin凝胶组的阴道粘膜上皮细胞均较完整,固有层组织仅轻度水肿;suramin凝胶不会促进炎症因子的释放;suramin凝胶组的阴道上皮细胞和基质细胞PCNA阳性表达率与生理盐水组无显著性差异。4.MD模拟表明分子结构非常相似的3个化合物与PAP248-286结合模式不同,分子结构趋向于立体的suramin能把PAP248-286完全包裹住,另外其改变PAP248-286单体结构的程度最大:suramin几乎与PAP248-286 上所有的氨基酸有氢键或疏水作用:氢键有19个,疏水作用数为45。研究结论1.suramin能紧密结合多肽PAP248-286,抑制其自我聚合形成淀粉样纤维SEVI。2.suramin阻断SEVI和HIV-1结合,拮抗其增强病毒感染能力。3.suramin在精液中分别联合不同作用机制的ARVs均具有协同抗病毒作用,且对生殖道细胞和淋巴细胞基本无毒性作用,对家兔阴道无明显致炎作用,有较高的安全性。

关键词： suramin 淀粉样纤维人类免疫缺陷病毒性传播杀微生物剂

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New anticancer drugs in Europe

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Chinese Medical Journal 1997年第4期110卷 58-69页

作者： Jean Pierre Armand Department of Medicine Institute Gustave Roussy Vilejuif France

ＮｅｗａｎｔｉｃａｎｃｅｒｄｒｕｇｓｉｎＥｕｒｏｐｅＪｅａｎＰｉｅｒｅＡｒｍａｎｄＦｏｒｔｈｅｎｅａｒｆｕｔｕｒｅ，ｓｙｓｔｅｍｉｃｃｈｅｍｏｔｈｅｒａｐｙｗｉｌｂｅｔｈｅｍａｉｎｓｔａｙｏｆｔｒｅａｔｍｅｎｔｉｎｍ... 详细信息

ＮｅｗａｎｔｉｃａｎｃｅｒｄｒｕｇｓｉｎＥｕｒｏｐｅＪｅａｎＰｉｅｒｅＡｒｍａｎｄＦｏｒｔｈｅｎｅａｒｆｕｔｕｒｅ，ｓｙｓｔｅｍｉｃｃｈｅｍｏｔｈｅｒａｐｙｗｉｌｂｅｔｈｅｍａｉｎｓｔａｙｏｆｔｒｅａｔｍｅｎｔｉｎｍｅｔａｓｔａｔｉｃｃａｎｃｅｒ．Ｉ...

关键词： ADVANCED BREAST-CANCER CLINICAL-TRIALS GROUP CELL LUNG-CANCER PHASE-I TRIAL ETOPOSIDE PHOSPHATE VINORELBINE IRINOTECAN AGENT IODODOXORUBICIN suramin

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Trypanosoma brucei rhodesiense infection in a Chinese traveler returning from the Serengeti National Park in Tanzania

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Infectious Diseases of Poverty 2018年第1期7卷 486-491页

作者： Qin Liu Xiao-Ling Chen Mu-Xin Chen Han-Guo Xie Qing Liu Zhu-Yun Chen Yao-Ying Lin Hua Zheng Jia-Xu Chen Yi Zhang Xiao-Nong Zhou National Institute of Parasitic Diseases Chinese Center for Disease Control and PreventionChinese Center for Tropical Diseases ResearchWHO Collaborating Centre for Tropical DiseasesNational Center for International Research on Tropical DiseasesMinistry of Science and TechnologyKey Laboratory of Parasite and Vector BiologyMinistry of HealthShanghai 200025China Fujian Medical University Union Hospital FuzhouFujian 350001People’s Republic of China Fujian Provincial Center for Diseases Control and Prevention FuzhouFujian 350000People’s Republic of China

Background:Human African trypanosomiasis(HAT)is one of the most complex parasitic diseases known to humankind.It usually occurs in endemic areas in Africa,but is occasionally detected in returning travelers and migrants in non-endemic countries.Case presentation:In August 2017,a case of HAT was diagnosed in China in a traveler returning from the Masai Mara area in Kenya and the Serengeti area in Tanzania.The traveler visited Africa from 23 July to 5 August,2017.Upon return to China,she developed a fever(on 8 August),and Trypanosoma brucei rhodesiense infection was confirmed by laboratory tests(on 14 August)including observation of parasites in blood films and by polymerase chain reaction.She was treated with pentamidine followed by suramin,and recovered 1 month later.Conclusions:This is the first imported rhodesiense HAT case reported in China.This case alerts clinical and public health workers to be aware of HAT in travelers,and expatriates and migrants who have visited at-risk areas in Africa.

关键词： Trypanosoma brucei rhodesiense Human African trypanosomiasis Imported infection China Treatment suramin Tanzania

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suramin ACTIVIY IN HUMAN HEAD AND NECK SQUAMOUS CELL CARCINOMA——Ⅱ.EFFECT OF suramin ON HUMAN HEAD AND NECK CARCINOMA XENOGRAFTS AND RELATED TOXICITY AND PHARMACOKINETIC STUDIES IN NUDE MICE

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山东大学学报(医学版) 1992年第4期 343-348页

作者：李安太王天铎栾信庸姜玉芳 G.A.M.S.Van Dongen B.J.M.Braakhuis G.B.Snow Amsterdam The Netherlands Dept.of Otolaryngology/Head and Neck Surgery Free University Hospital Amsterdam The Netherlands Dept.of Otolaryngology/Head and Neck Surgery Free University Hospital Amsterdam The Netherlands Dept.of Otolaryngology Affiliated Hospital of Shandong Medical University Dept.of Otolaryngology Affiliated Hospital of Shandong Medical University Dept.of Otolaryngology Affiliated Hospital of Shandong Medical University Dept.of Otolaryngology Affiliated Hospital of Shandong Medical University Dept.of Otolaryngology/Head and Neck Surgery Free University Hospital

In part Ⅰ of the study,we have demonstrated that suraminhas a marked antiproliferative effect on human head and neck squamous cellcarcinoma cell lines,In the present study,both toxicity and pharmacokineticstudies in nude mice were done.The treatment of nude mice bearing head andneck cancers with suramin showed that suramin had a minimal antitumor effect.The possible mechanism of suramin lacking antitumor effect is discussed.

关键词： suramin Head and neck neoplasms Transplantation heterologous Toxicity study Pharmacokinetic study Mice,nude

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